Académique Documents
Professionnel Documents
Culture Documents
-Oxidation
Florence Rajaretnam M.Sc., M.Phil.
Learning Objectives
After reading this chapter you should be
able to:
Describe the mobilization of fatty acids from adiposites
Trace out the pathway followed by glycerol and Fatty acids
Outline the pathway for activation & transport of FAs to the
mitochondrion for catabolism.
Describe the sequence of rxns involved in oxidation of FAs in the
mitochondrion.
Explain the rationale for the pathway of ketogenesis & identify the
major intermediates & products of this pathway.
2
Mobilization of Fatty acids from adipocytes.
When the energy supply from the diet is limited, the body
responds to this deficiency through the secretion of hormones like
glucagon, epinephrine or adrenocorticotropic hormones
3
These hormones activate an enzyme called hormone sensitive
triacylglycerol lipases.
8
Steps in -Oxidation
10
Therefore, a specialized carrier located in the inner
mitochondrial membrane transports the acyl group from the
cytoplasm into the mitochondrion.
11
2. The fatty acyl-carnitine is transported into the mitochondrial
matrix by carnitine cayl carnitine translocase.
12
13 Fig-1.1 Transport of Long-chain FAs into Mitochondria
Fig-1.1 Transport of Long-chain FAs into Mitochondria 14
Mitochondrial Oxidation of FAs
Takes place in three
stages Fig-1.2
15
In the 1st stage -oxidation Fig-1.3
2 carbons are cleaved at a time to form acyl-CoA
molecules,
starting from the carboxyl end
The chain is broken between the (2) & (3)
carbon atoms,
hence the name -oxidation
Formation of each acetyl-CoA requires
removal of 4 hydrogen atoms
from the fatty acyl moiety by dehydrogenases
16
In the 2nd stage of FA oxidation,
The acetyl groups of acetyl-CoA are
oxidized to CO2 in the TCA cycle mitochondrial
matrix
The first two stages of fatty acid oxidation produce
the reduced electron carriers NADH & FADH2,
w/c in the 3rd stage donate electrons to ETC;
through which the electrons pass to oxygen
with the concomitant phosphorylation of ADP to ATP
The energy released by fatty acid oxidation is
thus conserved as ATP
17
Fig-1.3. Overview of mitochondrial
long-chain FA metabolism
1) FA binding proteins (FaBP)
transport FAs across
the plasma membrane & bind them
in the cytosol
2) Fatty acyl CoA synthetase
activates FAs to fatty acyl CoAs
3) Carnitine transports the activated
fatty acyl group
into mitochondria
4) -oxidation generates
NADH, FAD(2H), & acetyl CoA
5) In the liver, acetyl CoA is
converted to ketone bodies
18
-Oxidation of Saturated FAs
Overview of - Oxidation Fig-2
Four Basic Steps:
4 enzyme-catalyzed rxns make up the first stage of FA
oxidation
Step I: Oxidation (unsaturation)- dehydrogenation:
Catalyzed by acyl-CoA dehydrogenase
Coenzyme for this rxn is
a flavoprotein FAD as a prosthetic group
FADH2 is oxidized;
in mitochondrial respiratory chain to give 2 ATP
19
Contd
Step II: Hydration:
Catalyzed by enoyl-CoA Hydratase (crotonase)
which helps the addition of H2O to saturate double
bond
Step III: Oxidation (-oxidation)- dehydrogenation
By -Hydroxyacyl CoA dehydrogenase & NAD+
Oxidation of NADH + H+ in respiratory chain gives 3
ATP
20
Step IV : Splitting of active acetate- (Chain breakage):
It is catalyzed by Thiolase (acyl-CoA acetyltransferase)
It splits acyl CoA into Acetyl CoA & Acyl CoA,
w/c is shorter than the first one by 2 carbon
atoms
The process is repeated Until the whole FA is
Broken into acetyl CoA;
w/c are then oxidized to CO2 & H2O in Krebs
cycle
21
22
How is the amount of ATP produced by the degradation of a fatty
acid calculated?
In order to obtain this information it would be very easy if we
follow thes steps:
1- The following formula may be used to calculate the number of
times the cycle of the reactions may occur till the total
degradation of a fatty acid to acetyl CoA
24
If we want to know the total amount of ATP obtained by the total
degradation of the fatty acid to CO2 and H2O, another two steps
are necessary:
25
Regulation of fatty acyl CoA degradation
Malonyl CoA is the principal regulator of the rate of -oxidation
reactions.
Malonyl CoA inhibits the entry of acyl groups into the
mitochondria.
Importance of -Oxidation
Source of energy:
Oxidation of FA is a major source of energy
to the body during starvation
Production of acetyl CoA:
Acetyl CoA is converted to several useful compounds:
e.g. cholesterol, acetyl choline fatty acids, Ketone
bodies etc. 26
Ketone bodies formation:
Formation of acetoacetyl CoA;
w/c is derived from oxidation of long chain acyl
CoA,
i.e. the last 4 carbon atoms, may be converted to;
Acetoacetic acid w/c is one of the ketone bodies
27
28
Synthesis of Ketone Bodies/Ketogenesis
In the liver, ketone bodies are synthesized
In the mitochondrial matrix
from acetyl CoA generated from FA oxidation
The thiolase rxn of FA oxidation, w/c converts;
acetoacetyl CoA to two molecules of acetyl CoA
is a reversible rxn,
although formation of acetoacetyl-CoA is not the favored
direction
It can, thus, when acetyl-CoA levels are high,
29
The acetoacetyl CoA will react with acetyl CoA Fig-15
to produce 3-hydroxy-3-methylglutaryl CoA (HMG-
CoA)
The enzyme that catalyzes this rxn is HMG-CoA
synthase
In the next rxn of the pathway,
HMG-CoA lyase catalyzes the cleavage of HMG-CoA to
form
acetyl CoA & acetoacetate
enters the blood
30
Acetoacetate can directly enter the blood or
it can be reduced by -hydroxybutyrate dehydrogenase
to
-hydroxybutyrate, which enters the blood
31
dehydrogenase rxn is readily reversible
interconvert's these two ketone bodies,
Under normal conditions,
the ratio of -hydroxybutyrate to acetoacetate in the
blood is 1:1
An alternate fate of acetoacetate is
spontaneous decarboxylation, a nonenzymatic rxn that
cleaves
acetoacetate into CO2 & acetone
Because acetone is volatile,
it is expired by the lungs or excreted in urine
32
Ketogenesis
33
Oxidation of Ketone Bodies as Fuels/Ketolysis
Acetoacetate and -hydroxybutyrate
can be oxidized as fuels in most tissues, including
skeletal muscle & brain,
certain cells of the kidney,
cells of the intestinal mucosa
Cells transport both acetoacetate & -hydroxybutyrate
from the circulating blood into the cytosol, &
into the mitochondrial matrix
34
-hydroxybutyrate is oxidized back to acetoacetate
by
-hydroxybutyrate dehydrogenase
This rxn produces NADH
Subsequent steps convert
acetoacetate to acetyl CoA
In mitochondria,
acetoacetate is activated to acetoacetyl CoA;
by succinyl CoA:acetoacetate CoA transferase
/thiotransferase
As the name suggests, CoA is transferred from
succinyl CoA to acetoacetate
35
Although the liver produces ketone bodies, it does not use
them,
b/c this thiotransferase enzyme is not present in
sufficient quantity
36
37
When the rate of formation of ketone bodies is greater than the
rate of their use, their levels begin to rise in the blood (ketonemia)
and eventually in the urine (ketonuria).
This state is known as ketoacidosis or Ketosis.
Extreme acidosis can lead to coma & in some cases death
During Ketosis acetone is eliminate by the breath.
38
Oxidation of FAs With Odd No of C-Atoms
39
Formation of propionyl CoA from odd-chain FAs
45
Fig-10b. Regulation of -Oxidation
1. Hormones control the supply of fatty acids in the blood.
2.CPT- I is inhibited by malonyl CoA, w/c is synthesized by acetyl CoA
carboxylase
AMP-PK is the AMP-dependent protein kinase
3.The rate of ATP utilization controls the rate of the ETC,
w/c regulates the oxidative enzymes of -oxidation and the TCA cycle
46
An additional type of regulation occurs at CPTI Fig-
10b-2
CPT I is inhibited by malonyl CoA,
w/c is synthesized by Acetyl CoA carboxylase
47
-oxidation is strictly an aerobic pathway
Dependent on O2 & Mitochondria
Tissues that lack mitochondria, such as RBCs,
Cant oxidize FAs by -oxidation
FAs also do not serve as
a significant fuel for the brain
They are not used by adipocytes, whose function is;
to store TAGs to provide a fuel for other tissues
Those tissues that
Dont use FAs as a fuel, or use them only to a limited
extent, are able to use ketone bodies instead
48